Resting coronary blood flow and regional myocardial perfusion are normal despite severe coronary stenosis but maximal coronary flow or coronary flow reserve is reduced by mild coronary stenosis. Measurement of relative coronary flow increase and regional perfusion during the maximal hyperemia following intracoronary injection of contrast media has provided a quantitative measure of regional coronary flow reserve and stress induced regional malperfusion in experimental animals and man. Such measurements permit assessment of the hemodynamic significance of coronary stenoses before they become severe enough to reduce resting coronary flow. The first experimentally validated (open chest dogs) and clinically applicable method (over 100 patients) based on these principles was developed in this laboratory. It consists of imaging the myocardium at rest and during hyperemia when flow in a non-constricted artery increases normally but flow in a stenotic artery increases to lesser degree or not at all, thereby producing regional malperfusion and a defect in the myocardial image. However, the method has some technical limitations and has not been defined in terms of coronary dynamics in intact, exercising, chronically instrumented animals. This project will describe for the first time in exercising animals (treadmill) the effects of coronary stenosis simultaneously on regional coronary flow and flow reserve, regional stress induced malperfusion, distal coronary pressure, stenosis pressure gradient and gradient-flow relationships, compensatory coronary vasodilation, myocardial lactate and potassium metabolism, regional left ventricular wall thickening and electrocardiographic S-T changes. Our original method will be further developed into (a) a more accurate non-invasive method utilizing myocardial imaging of a new intravenously injected radionuclide, Thallium-201 (b) a more accurate invasive method utilizing a high quality videodensitometer system being installed in this laboratory. Thus, this project will lead to highly accurate non-invasive and invasive methods, experimentally validated and routinely applicable in clinical laboratories for quantifying the hemodynamic severity of coronary stenoses, regional coronary flow reserve and stress induced regional malperfusion.